Over-active and poor connectivity in brain circuitry in Down syndrome

Over-active and poor connectivity in brain circuitry in Down syndrome

A team of researchers have studied the neural basis of intellectual disability in mice with Down syndrome and has discovered that the neural networks of brain circuits relevant to memory and learning are over-activated and that the connectivity of these circuits is poor.

The researchers have also observed that neural activity during sleep is abnormal and probably interferes with memory consolidation. The study has even identified biomarkers in brain rhythms that can predict memory deficits in the mice which are corrected by chronic treatment with a natural component of green tea, epigallocatechin gallate, which other studies have already shown to improve executive function in adults with Down syndrome.

"These results suggest that both hyperactivity of neuronal networks and deficiencies in the connectivity of specific brain circuits are possible dysfunctional mechanisms that contribute to memory deficits in Down syndrome and, therefore, offer new therapeutic possibilities for treating intellectual disability," explains the senior author.

To date, it had been recognised that epigallocatechin gallate corrects certain alterations at the molecular and cellular levels derived from the trisomy of chromosome 21 that are associated with cognitive deficits in Down syndrome. However, a dynamic description of the actions of epigallocatechin gallate on neural activity during distinct brain states was lacking. This is, therefore, the first time that anyone has looked at how mouse brain responds to chronic treatment with epigallocatechin gallate at a functional level in trisomy conditions.

The study involved recording neuronal activity simultaneously in two brain regions critical for learning and memory, the prefrontal cortex and the hippocampus, in trisomic and non-trisomic mice during periods of rest while awake, asleep, and during the performance of a simple memory task.

During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal–hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing.

During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal–hippocampal functional connectivity. 

The data was collected before and after one month of treatment with epigallocatechin gallate, and the alterations in the activity of the neuronal networks in the two regions as well as the connectivity of the circuitry correlating with memory capacities were analysed and found to have been corrected with the green tea extract.

According to the senior author, "This study provides an in-depth description of the neurophysiological abnormalities present in different brain states in Down syndrome model mice and provides the keys for understanding the cellular mechanisms underlying the improved executive function observed in people with Down syndrome after chronic treatment with epigallocatechin gallate".